Access to C(sp3) borylated and silylated cyclic molecules: hydrogenation of corresponding arenes and heteroarenes

This paper presents a simple and cost-effective hydrogenation method for synthesizing a myriad of cycloalkanes and saturated heterocycles bearing boryl or silyl substituents. The catalyst used are heterogeneous, readily available, bench stable, and recyclable. Also demonstrated is the application of the method to compounds that possess both boryl and silyl groups. When combined with Ir-catalyzed sp2 C–H borylation, such hydrogenations offer a two-step complementary alternative to direct sp3 C–H borylations that can suffer selectivity and reactivity issues. Of practical value to the community, complete stereochemical analyses of reported borylated compounds that were never fully characterized are reported herein.


Introduction
Organoboron compounds are oen pivotal intermediates in the synthesis of natural products, biologically relevant molecules and compounds used in material science. 1 Such broad applications come from the ability of C-B bonds to be readily transformed to C-OH, C-NH 2 , C-C bonds, etc.Additionally, boryl groups present on sp 3 carbons can undergo couplings with retention or inversion of stereochemistry, Matteson homologation reactions, etc. 2 Owing to their synthetic utility, the pursuit of new methods and strategies for making borylated compounds is an active area of research.
Among the various borylation methods, catalytic sp 2 C-H borylations are widely used for the preparation of borylated arenes and heteroarenes.In contrast, catalytic sp 3 C-H borylations to afford borylated cycloalkanes and saturated heterocycles are relatively underdeveloped.Many sp 3 C-H borylation methods are highly substrate limited requiring the presence of a directing group (e.g.][5][6] In recent years, some of these restraints have been eased.The Hartwig group has established directing group free sp 3 C-H borylation chemistry that encompasses a broader substrate scope, including alkanes, ethers, protected amines, alcohols, and carbocycles.Their method affords good selectivity and when executed with an excess of boron reagent good reactivity. In addition, all reported examples were run in cyclooctane.As the authors note, this restricted functionalization of polar molecules due to poor solubility. 7Schley and coworkers were able to overcome the limitation of excess of boron reagent through the thoughtful application of dipyridylarylmethane as ligand. 8In an alternative strategy, sp 3 C-H borylated compounds can be accessed by hydrogenating corresponding borylated arenes, which themselves can be obtained via iridium catalyzed sp 2 C-H borylations.0][11][12][13][14][15][16][17][18][19][20] However, none of these reports demonstrated the hydrogenation on borylated or silylated arenes or heteroarenes.2][23][24][25] In similar work, Zeng showed hydrogenation of borylated arenes and heteroarenes using a related Rh-catalyst (Fig. 1). 26][29] Glorius also reported hydrogenations using Rh/C in their optimization studies on six borylated substrates (ve benzenes and one pyridine). 21Catalysis with Rh/C showed full conversion with TBS protected 4-Bpin phenol, but as the authors noted the other arenes tested and the pyridine gave diminished yields (17-33%).Separately, 10 Rh/C catalyzed hydrogenation of six silylated benzenes were examined.It was reported that two of the six gave 0% of the corresponding cyclohexanes, but three substrates were saturated in 25, 35, and 40% yields respectively.In contrast, the hydrogenation of n-hexyl ether of 4-TMS-phenol was achieved in 90% yield with Rh/C in hexane (vs.16% in EtOH) and could be further optimized up to 97% using Rh/ Al 2 O 3 .
Other recent reports on saturating arenes and heteroarenes that do not bear boryl or silyl substituents include the work of Handa, who used [Ir(cod)Cl] 2 to hydrogenate phosphine oxide scaffolds with Ir nanoparticles being the active catalyst. 302][33] The hydrogenation of uoropyridines using Pd(OH) 2 , in acidic media has also been reported. 34hile we considered all prior art cited above, Glorius' results motivated us to fully evaluate bench stable and commercially available Rh-catalysts, e.g.Rh/C or Rh/Al 2 O 3 , or other standard hydrogenation catalysts against a larger substrate set of arenes and heteroarenes with boryl or silyl substituents.We were further inspired by Glorius' recent report on hydrogenation of arenes that were bisfunctionalized with germyl and boryl, and germyl and silyl, 35 and sought to hydrogenate previously unexplored heteroarenes bearing both boryl and silyl substituents.

Results and discussion
As the catalytic hydrogenations of pyridines using Rh/C is well established, 36 we began our study by subjecting an ethanolic mixture of 3-borylated pyridine 1a to 5% Rh/C under a hydrogen atmosphere (Table 1; entry 1).As piperdines are known to poison Rh-catalysis 36,37 and since pyridinium salts hydrogenate more readily than the free base, 38 HCl was added to the reaction mixture.Aer 1 h, the pyridine ring was fully saturated to afford the desired borylated piperidine (2a) along with the deboronated product (3a).Rhodium on alumina (entry 2) afforded a similar mix of 2a and 3a, but the reaction was incomplete aer 2 hours.Though platinum oxide has long been used to hydrogenate pyridines, reactions catalyzed by Pt 2 O and Pt/C met with an increased amount of deboronation (entries 3 and 4).
Catalytic hydrogenations of pyridines with palladium typically demand higher temperatures (70-80 °C) and higher catalyst loads, 39 so it was not entirely surprising that 10% Pd/C failed to effect hydrogenation (entry 5).W2 RANEY® nickel 40 and Ru-catalysts 41 were not tested given the precedent for hydrogenations of pyridines with those catalysts requiring pressures > 1000 psi.
With Rh/C proving fastest at hydrogenating 1a, reactions with this catalyst were screened against different solvents (Table 2).In addition to ethanol, 1a could be hydrogenated in methanol, dichloromethane, dioxane, and THF.Yields of 2a were observed to be in order of ethanol/methanol > THF > dioxane > dichloromethane.This trend is consistent with previous reports on hydrogenations of non-polar substrates in polar solvents, where it has been shown that higher yields correlate to higher activity coefficients. 42Methanol was chosen as the reaction solvent because of the greenness of the solvent. 43Unfortunately, with all solvents deboronation remained a problem, with 3a being the only observed product when the reaction was run in dichloromethane for 36 hours.As metal mediated protiodeboronation by Brønsted acids and Lewis acids is well known, 44 the reaction was run without HCl (Table 2; entry 2).This led to no reaction.Reducing the amount of conc.HCl in the reaction or using dry HCl (Table S1 †) resulted in similar 2a : 3a ratios as those observed in entry 1, Table 1.Other Brønsted and Lewis acids were also tested (Tables S1 and S2 †), but none solved the deboronation problem.Lastly, we explored the idea that by starting with a halogenated 3-borylpyridine the reaction conditions would in situ generate 1 equiv. of HX, which would immediately form the pyridinium and not promote deboronation.Thus 3-bromo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)pyridine (2b) was hydrogenated under the standard, albeit HCl free, conditions.Though debromination and hydrogenation occurred as predicted, deboronation was not eliminated.Unable to eliminate deboronation, we reevaluated the early catalyst screening data.Catalysis using Rh/Al 2 O 3 (entry 2, Table 1) was slower than Rh/C, but afforded a better ratio of 2a to 3a.Therefore, as we looked at the hydrogenation of additional borylated pyridines, Rh/Al 2 O 3 was employed as catalyst and reactions were run for 16 h.As shown in Table 3 (entries 2-5) 2c, 2d, 2e, and 2f were all formed >80% yield with no deboronation.Of note was the hydrogenation of 1f, which was carried out without the addition or in situ generation of a Brønsted acid.Presumably, the methyl groups at C2 and C6 inhibit poisoning of the catalyst.Furthermore, 2f was formed as single diastereomer, the stereochemistry of which as determined to be all cis by oxidizing the boronate ester to a hydroxy group and comparing that product to analogous literature compounds. 45,46ydrogenation of different 5 membered borylated heterocycles were then investigated (Scheme 1).Under Rh/C catalysis, N-Boc-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrrole (1g) was successfully hydrogenated (73% yield) on 1 gram scale without any observable loss of the Bpin.As Pd/C has been shown to selectively hydrogenate the pyrrole ring on nicotyrine, 47 the catalytic hydrogenation of 1g was also run with 10% Pd/C and 2g was afforded in 82% yield.We also attempted a one pot Ir-catalyzed borylation/hydrogenation sequence using Boc-pyrrole as the starting substrate.In practice, running the hydrogenation step on the crude borylation mixture was not successful as only 1g was observed.Nonetheless, it should be noted that the CH borylation of Boc-pyrrole gives 1g in 90% yield.Thus, the 74% two-step combined yield of 2g from Bocpyrrole compares favorably to 54% yield obtained in the Ircatalyzed sp 3 C-H borylation of Boc-pyrrolidine.Moving on to other heterocycles, hydrogenation of 2-borylated furan (1h) occurred with 100% conversion to 2h. Isolation of 2h (89%) was complicated by the presence of HOBpin or oligomers thereof (∼8%).In this case, Rh/C is not as efficient as the Glorius catalyst, which affords 2h from 1h in 98% yield. 21,26t is worth nothing that when hydrogenating 1h at 2.5 mmol scale the catalyst could be recycled ve times with reproducible results aer each cycle.Direct sp 3 Ir-catalyzed CH borylations of tetrahydrofuran gives the C-3 borylated product, 7 in contrast, the sp 2 Ir-catalyzed CH borylation of furan gives the C-2 borylated product.This highlights the potential for direct borylation and borylation/hydrogenation approaches to be complementary.
Hydrogenations of methyl substituted 1i, benzofuran 1j and dibenzofuran 1k were then carried out.Compound 2i was obtained in 74% yield as a 97 : 3 cis/trans mixture and as before a minor amount of boron byproduct (∼6%) was present in the isolated material.The cis stereochemistry of the major product was ascertained by COSY and 1D NOE NMR.Interestingly, hydrogenation of 1j generated the fully saturated borylated octahydrobenzofuran 2j again contaminated by the boron byproduct (78 : 22 by NMR).Compound 1k underwent full conversion affording 2k with 8% of the deboronated product.Though a minor product, the presence of the deboronated material made purication of 2k challenging and thus pristine 2k was isolated in only 38% yield.We were also able to generate 2l as an octahydroindole in 97% yield.The stereochemistry of hydrogen a to the nitrogen was found to be cis with the bridgehead hydrogen by 1D-NOE experiments.An unprotected borylated indole and a 2-borylated methylthiophene failed to produce saturated products 2m and 2n respectively, only starting material observed by 1 H-NMR in both cases.
The hydrogenation of borylated arenes was also carried out (Scheme 2).All borylated arenes tested were easily hydrogenated with Rh/C and functional groups like esters, methoxy, alkyl, triuoroalkane and alcohols were well tolerated.For compounds 2q, 2r, 2s, 2t, and 2u low ratios of cis and trans products were obtained with the cis diastereomers being major.The assignment for 2q was made by comparisons to a known silylated derivative. 48To do so for compounds 2r, 2t, and 2u, a Isolated yields and relative stereochemistry shown, starting material (0.5 mmol), ethanol (5 mL).b Isolated as a mixture.c Run at 0.3 mmol scale.
each of these products were oxidized to their alcohols, 49 which were then compared to previously reported cis and trans alcohols.It is worth noting that when 2u was generated using caac-Rh-2 as the catalyst, a yield of 55% yield was observed vs. the 68% with Rh/C.Diastereoselectivity was similar in both cases (∼6 : 1). 26The major stereoisomer of 2s being cis was conrmed using 1D-NOE.The major stereochemistry of bisborylcyclohexane 2v was made by direct comparison to literature data. 50arbon-silicon bonds, similar to carbon-boron bonds, are also versatile as they can be transformed to various functional groups such as hydroxy, amine, halogen and aryl. 51Thus, we sought to apply the same chemistry to organosilicon bearing heterocycles (Scheme 3).TMS-substituted pyridines 2-TMS 1w and 4-TMS 1x were easily hydrogenated with Rh/C and Rh/Al 2 O 3 respectively, demonstrating the utility of both these catalysts for such substrates.Compound 1w was hydrogenated as a salt of camphor sulphonate.This was to see whether adding an optically active acid could induce chirality in the hydrogenated product.This proved not to be the case as a 1 : 1 mixture of enantiomers was obtained.Surprisingly, 1y, which only differs from 1x by the position of the TMS group gave 2y as a 1 : 5 mixture with the desilylated material being major as determined by LCMS and 19 F-NMR.Two siloxanes, 1z and 1aa were also tested.Compound 1z presented the opportunity to probe complementary reactivity beyond just the ability to saturate siloxane containing hetero arenes.As Rh/C led to the saturation of both rings of 1j, for 1z we employed Pd/C to see if 2,3-dihydrobenzofuran 2z could be formed selectively. 25,52,53We were delighted to see this hypothesis realized.Catalytic hydrogenation of arene 1aa showcased how catalyst choice matters.For this substrate, Pd/C only returned starting material.Rh/C saturated the ring, but the siloxane was lost.In contrast, Rh/Al 2 O 3 successfully provided 2aa in 78% yield. 54ual functionalized compounds that incorporate both silyl and boryl group have shown potential in facilitating diverse reaction pathways due to their orthogonal reactivity.An example of such reactivity was demonstrated by Hartwig where Bpin was converted to a Boc protected amine without compromising silyl groups.In another example, the silyl group was manipulated without compromising the Bpin group. 55iven such demonstrations of Si/B dual functionality, we prepared and then hydrogenated 1ab-1af under Rh/C catalysis (Scheme 4).To drive the hydrogenation of pyrrole 1ab to full conversion, increasing the reaction time to 48 h and doubling the catalyst loading to 4 mol% was required.This enabled isolation of 2ab in 93% yield with a high cis : trans ratio (96 : 4).The cis conguration was conrmed by NOE and 2D NMR experiments.Hydrogenation of 2-bromo-4-(Bpin)-6-(TMS) pyridine 1ac was also carried out.As seen earlier, ring saturation was accompanied by debromination affording 2ac as its HBr salt.Compound 2ac was isolated in 46% yield by precipitating out the product using ethyl acetate.The 100% cis stereochemistry was determined by 1D-NOE.

Conclusion
In summary, Rh/C, Rh/Al 2 O 3 , and other readily available catalysts can affect the hydrogenation of borylated and silylated arenes and heteroarenes.Demonstrations of these catalysts to substrates bearing both boryl and silyl group were also shown to be viable.Catalyst selection is oen key to successful hydrogenations, especially for 5-and 6-membered heterocycles.In some cases, minimizing unwanted loss of the boron or silicon substituent can also be achieved through catalyst choice.The scope, including limitations disclosed, and comparisons made to the pioneering work of Glorius and Zheng can help guide practitioners as to whether to employ more complex Rhcatalysts or those tested herein.Spectroscopic data reported herein for new molecules as well as previously described compounds where full characterization data were lacking may also prove valuable for those who nd those compounds of interest.

General remarks
Unless indicated otherwise all reactions were carried out in oven-dried glassware with magnetic stirring and monitored by GC-MS or 1 H-NMR/ 19 F-NMR.Tetrahydrofuran was freshly distilled from sodium/benzophenone under nitrogen.Diisopropylamine was freshly distilled from calcium hydride.n-BuLi was used as a 2.5 M solution in hexanes.Flash column chromatography was performed with silica gel (230-400 mesh).Spectra taken in CDCl 3 were referenced to 7.26 ppm in 1 H NMR and 77.2 ppm in 13 C{ 1 H} NMR, C 6 D 6 was referenced to 7.16 ppm in 1 H NMR and 128.4 ppm in 13 C{ 1 H} NMR, C 7 D 8 was referenced to 7.17 ppm in 1 H NMR and 128.9 ppm in 13 C{ 1 H} NMR, CD 2 Cl 2 was referenced to 5.30 ppm in 1 H NMR and 53.5 ppm in 13 C{ 1 H} NMR.Resonances for the boron-bearing carbon atom were not observed due to quadrupolar relaxation.All coupling constants are apparent J values measured at the indicated eld strengths in Hertz (s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, ddd = doublet of doublet of doublets, bs = broad singlet).
High-resolution mass spectra (HRMS) were obtained at the Michigan State University Mass Spectrometry Service Center using electrospray ionization (ESI+ or ESI−) on quadrupole time-of-ight (Q-TOF) instruments.Low resolution mass spectra were obtained on GCMS-QP2010 SE Shimadzu instrument.Melting points were measured in a capillary melting point apparatus and are uncorrected.
General procedure A for synthesis of starting materials via iridium catalysis (1d-1g and 1z) In a nitrogen lled glove box in a vial (5 mL)/round bottom (50 mL) loaded with a stir bar was added bis(1,5-cyclooctadiene)dim-methoxydiiridium(I), bis(pinacolato)diboron or bis(trimethylsiloxy)methylsilane, di-tert-butylbipyridine followed by addition of substrate in THF.The vial/round bottom was closed, removed from the glove box, connected to a Schlenk line, and placed in an oil bath.The solution was stirred under nitrogen at 70-80 °C for 16-48 h.The reaction mixture was concentrated by rotary evaporation and puried by passing through a silica plug or ash column chromatography.
Test 2. The recovered catalyst from test 1 was used again with (500 mg, 2.5 mmol) with 10 mL ethanol for 4 h.The catalyst was recycled by ltration using a sintered funnel and washed with EtOAc.Aer purication of the ltrate, the solvent was removed by rotary evaporation to yield a clear oil (80% conversion to product, 414 mg of mixture, 82% crude yield).
Test 3. The recovered catalyst from test 2 was used again with (500 mg, 2.5 mmol) with 10 mL ethanol for 6 h.The catalyst was recycled by ltration using a sintered funnel and washed with EtOAc.Aer purication of the ltrate, the solvent was removed by rotary evaporation to yield a clear oil (100% conversion, 376 mg, 75% yield).
Test 4. The recovered catalyst from test 3 was used again with (500 mg, 2.5 mmol) with 10 mL ethanol for 5 h.The catalyst was recycled by ltration using a sintered funnel and washed with EtOAc.Aer purication of the ltrate, the solvent was removed by rotary evaporation to yield a clear oil (100% conversion, 421 mg, 84% yield).
Test 5.The recovered catalyst from test 4 was used again with (500 mg, 2.5 mmol) with 10 mL ethanol for 5 h.Aer purication, the solvent was removed by rotary evaporation to yield a clear oil (100% conversion, 427 mg, 84% yield).

Table 1
Hydrogenation catalysts screening a

Table 2
Solvent screen for hydrogenation a b Relative composition determined by 1 H-NMR.c Run without HCl.